P1167: TREATMENT OF RELAPSED/REFRACTORY HGBCL WITH MYC REARRANGEMENT: A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY OF PC-002(SEPB)，A FIRST-IN-CLASS INHIBITOR OF DEUBIQUITINASES TARGETING MYC DEGRADATION
Authors: Sung-Soo Yoon, Zhiming LI, Keshu Zhou, Xiaoxi Zhou, Ye Guo, Huilai Zhang, Ki-Seong Eom, Seok Jin Kim, Sung Yong Oh, Sungnam Lim, Hagop Youssoufian, Vernon C Jiang, Zanchun Huang, Georgina Kilfoil, Xin Wang, Zhixiang Cao, Xiang LI, Alexander Wu, Yiyou Chen, Yuqin Song
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: In human B-cell tumors, c-Myc rearrangements involving 8q24 is a hallmark of Burkitt lymphoma and other high-grade B cell lymphomas (HGBCL). Several studies have shown that c-Myc-driven lymphomas can be suppressed upon c-Myc inhibition. However, c-Myc is considered to be an “undruggable” oncoprotein due to its structure and a lack of kinase activity. C-Myc is a short-lived protein and its degradation is mediated through the ubiquitin-proteasome system. Therefore, modulation of deubiquitination catalysis process may provide an efficient way for reducing the stability of c-Myc proteins. PC-002 (also known as Sepantronium Bromide, SepB) is a small molecule survivin suppressant with antitumor activity against a variety of tumor types. Recently, we discovered that PC-002 has another novel mechanism targeting cancers with N-Myc gene amplification. PC-002 inhibits the deubiquitinase activity of ubiquitin-specific proteases (USPs), which leads to N-Myc protein degradation. Similar effect has also been observed with c-Myc protein (unpublished data). Preclinically, PC-002 shortens the half-life of c-Myc protein, induces rapid apoptosis of cells with c-Myc rearrangement and rapid tumor regression in mice with established c-Myc–driven lymphoma xenograft. The discovery prompted us to initiate this Phase 2 proof-of-concept clinical trial in patients with relapsed/ refractory c-Myc rearranged HGBCL, including Burkitt Lymphoma (https://clinicaltrials.gov/ ct2/show/NCT05263583). Aims: The aim of this trial (https://clinicaltrials.gov/ct2/show/NCT05263583) is to study safety and efficacy of PC-002 as monotherapy for c-Myc rearranged HGBCL, including Burkitt Lymphoma. Methods: NCT05263583 is a multicenter, open-label, Phase 2 dose-finding study of PC-002 (Sepantronium Bromide, SepB) in patients with relapsed/refractory HGBCL and Burkitt’s lymphoma with c-Myc rearrangement. Patients will be treated with escalating doses of single-agent PC-002 administered by continuous intravenous infusion for 168 hours in 21-day cycles at two dose levels. The primary objective is to determine the safety, tolerability and recommended Phase 2 dose (3.6 and 4.8mg/m2/day) of PC-002. Cohorts of three patients will be enrolled at each dose level for PC-002 with expansion to six patients, if necessary, to assess toxicity. An additional 6 patients will be enrolled at the RP2D. Secondary objectives are Objective Response Rate (ORR), Duration of Response (DoR), Clinical Benefit Rate (CBR), Overall Survival (OS) and Progression-Free Survival (PFS). Exploratory objectives are aimed to measure PC-002 exposure and its relationship to clinical outcome and to assess the relationship between biomarkers and PC-002 efficacy. Results: As of 28 February 2023, 3 patients with a median age of 33 years (range 19-67 years) had received ≥ 2 cycles of dosing. Two of the patients (2 males) have Burkitt Lymphoma and one (female) has HGBCL (DLBCL-TH). No DLT event was occurred. 1 drug-unrelated SAE was reported. Preliminary assessment by image analysis showed partial response in 2 patients with relapsed/refractory Burkitt Lymphoma at the starting dose of 3.6 mg/m2/day. ORR of the 3 patients in Cohort 1 is 66.7% after 2 cycles of 3.6 mg/m2/day dose (2 PRs). Summary/Conclusion: At the time of abstract submission, the 1st cohort of 3 patients have completed at least two cycles of dosing. PC-002 is generally well-tolerated at 3.6 mg/m2/day and has been cleared by SRC to the next cohort of RP2D at 4.8 mg/m2/ day. Preliminary assessment by image analysis showed partial response in 2 pts with relapsed/refractory Burkitt Lymphoma at the starting dose of 3.6 mg/m2/day. ORR of the 3 patients in Cohort 1 is 66.7% after 2 cycles of 3.6 mg/m2/day (2 PRs). Keywords: Burkitt’s lymphoma, MYC, relapsed/refractory, DLBCL